1. Field of the Invention
The present invention relates to a novel cephalosporin compound represented by the following general formula (I): ##STR2## , its pharmaceutically acceptable non-toxic salt, physiologically hydrolyzable ester, hydrate and solvate, and isomer thereof,in which
R.sup.1 represents hydrogen or an amino-protecting group, PA1 R.sup.2 and R.sup.3 can be identical or different and each represent hydrogen or a hydroxy-protecting group, or PA1 R.sup.2 and R.sup.3 together can form a diol-protecting cyclic group, PA1 R.sup.4 represents hydrogen or a carboxyl-protecting group, PA1 R.sup.5 represents hydrogen, C.sub.1-4 alkyl, alkoxycarbonyl, carboxyl or sulfomethyl, PA1 R.sup.6 represents hydrogen, amino or substituted amino, and PA1 R.sup.7 represents C.sub.1-4 alkyl, amino or substituted amino, or PA1 R.sup.5 and R.sup.6 together with the carbon atoms to which they are attached may form a 3 to 7-membered cyclic group, or PA1 R.sup.6 and R.sup.7 together with the carbon and nitrogen atoms to which they are attached can form a 3 to 7-membered heterocyclic ring which may optionally contain additional heteroatoms such as nitrogen and/or oxygen and which may be substituted with the substituent selected from C.sub.1-4 alkyl, amino and substituted amino, and PA1 Q represents CH or N. PA1 R.sub.5 represents a group having the following general formula (B-1) or (B-2), ##STR5## R.sub.6 represents lower alkenyl, a N-containing 5- or 6-membered heterocyclic group which may be substituted, acylamino, or lower alkyl which may be substituted, PA1 R.sub.7 and R.sub.8 can be identical or different and each represent hydrogen, lower alkyl, amino, acylamino, carboxyl, carbamoyl, thiocarbamoyl or lower alkoxycarbonyl, PA1 R.sub.9 and R.sub.10 independently of each other represent lower alkyl, and V' and W' can be identical or different and represent a group --CH.dbd. or --N.dbd.. PA1 R.sub.12 represents C.sub.1-4 alkyl, C.sub.3-4 alkenyl, C.sub.3-4 cycloalkyl, substituted or unsubstituted amino, or substituted or unsubstituted phenyl, PA1 R.sub.13 represents hydrogen or C.sub.1-4 alkyl, and PA1 Q" represents CH or N.
The present invention also relates to a process for preparation of the compound of formula (I), as defined above, and to a pharmaceutical composition containing the compound of formula (I) as an active ingredient.
2. Background Art
Cephalosporin antibiotics have been widely used for treating diseases caused by pathogenic bacteria in human and animals and are particularly useful for treating diseases caused by bacteria which are resistant to other antibiotics such as penicillin compounds and for treating penicillin-hypersensitive patients. In most cases, it is preferable to use antibiotics which are active against both of gram-positive and gram-negative microorganisms. However, it has been well known that an antimicrobial activity of such cephalosporin antibiotics is greatly influenced by the substituent on 3- or 7-position of the cephem nucleus. Accordingly, it has been attempted to develope an antibiotic compound which shows a high antibacterial activity against a broad range of gram-positive and gram-negative strains and is very stable to .beta.-lactamse produced by various gram-negative strains and is also very stable in the living tissues. As a result thereof, heretofore, numerous cephalosporin antibiotics wherein various substituents are introduced into the 7-.beta. acylamino moiety and the 3-position of cephem nucleus have been developed.
For example, Japanese Laid-open Patent Publication No. (sho) 54-9296 very broadly discloses a cephalosporin derivative represented by the following general formula (A) having a substituent A on the 3-position of cephem nucleus: ##STR3##
In the specification of said Japanese Laid-open Patent Publication, it is generally disclosed that the substituent A on the 3-position is hydrogen, alkyloxy or alkenyloxy group which can be optionally substituted, halogen, or a --CH.sub.2 Y group wherein Y represents hydrogen, halogen or a residue derived from nucleophilic compounds such as --SR, and particularly, when Y is --SR, R is a 5 to 8-membered heterocyclic group which can be substituted. In this patent specification, as the specific example of the 5- to 8-membered heterocyclic group pyridyl or pyrimidinyl group which can be substituted is mentioned but there is no mention of 3-substituted 4-aminopyrimidinium group in a quaternary form as present in the compound of the present invention.
Meanwhile, European Patent Application No. 87304896.1 of Mitzyoshi et. al., discloses a cephalosporin compound represented by the following general formula (B): ##STR4## in which R.sub.4 is amino which may be protected,
In the specification of said Japanese Laid-open Patent Application, as the substituent on 3-position various heterocyclic groups including the groups of formulae (B-1) and (B-2), which may be substituted with hydrogen, lower alkyl, amino, etc., are described. In this specification, however, only alkyl-substituted pyrimidiniumthiomethyl group is specifically mentioned, which is completely distinguished from 3-substituted pyrimidiniumthiomethyl group having an amino group on 4-position.
Thus, the present inventors have extensively studied to develop cephalosporin antibiotics having a potent antimicrobial activity and a broad antibacterial spectrum. As a result, we have succeeded in developing cephalosporin compounds represented by the following general formula (C) having various 4,6-diaminopyrimidinium moiety on C-3 position (see, Korean Patent Nos. 47728, 47754, 47755 and 47756): ##STR6## in which R.sub.11 represents C.sub.1-4 alkyl, C.sub.3-4 alkenyl, C.sub.3-C4 alkynyl or a group C(R.sup.A)(R.sup.B COOH,
However, in the specifications of the above prior patents by the present inventors the compounds having a substituted aminopy-rimidiniumthiomethyl group in quaternary form are described, but there is no mention and suggestion on the compounds which can contain (Z)-2-(2-aminothiazol-4-yl)-2-(.alpha.-carboxy substituted phenylmethoxyimino)acetamido group on 7-position as described in the present invention.
Meanwhile, PCT/JP86/00140 discloses the cephem compound represented by the following general formula (D): ##STR7## in which
R.sup.14 represents hydrogen or an amino-protecting group,
R.sup.15 and R.sup.16 represent hydrogen, methyl, carboxyl, protected carboxyl or oxygen atom,
R.sup.17 and R.sup.18 represent hydrogen or oxygen atom,
R.sup.19 represents hydrogen or a carboxyl-protecting group,
a, b and c are an integer of 0 or 1, and
X represents hydrogen, hydroxyl or a group of formula ##STR8##
The specification of the above PCT application broadly describes the compounds having the substituent (Z)-2-(2-amino-thiazol-4-yl)-2-(.alpha.-carboxy substituted phenylmethoxyimino)acetamido group on 7.beta.-position as described in the present invention and also having a heterocyclothiomethyl group, particularly triazolopyrimidylthiomethyl, thiazolopyrimidylthiomethyl, and the like group, on C-3 position. However, such groups are completely different from 4-amino-3-substituted pyrimidiniumthiomethyl group in quaternary form as in the present invention. In addition, there is no mention or suggestion on such quaternary group.
In addition, European Patent Application No. 87308525.2 describes the cephem compound represented by the following general formula (E): ##STR9## in which
R.sup.24 represents hydrogen, or C.sub.1-4 alkyl substituted with 1 to 3 halogen atom(s),
R.sup.25 and R.sup.26 represent hydrogen or a carboxyl-protecting group,
R.sup.27 represents hydrogen or an amino-protecting group,
R.sup.28 and R.sup.29 represent hydroxy or substituted hydroxy, or R.sup.28 and R.sup.29 together form a protected cyclic diol group,
Z represents &gt;S or &gt;S.fwdarw.O, and
a dotted line denotes 2-cephem or 3-cephem compound.
However, in the above European patent the substituent introduced into C.sub.3 -position is different from the C-3 substituent of the present invention.
Thus, the present inventors have attempted to develop a compound having more potential antibacterial activity on the basis of the fact that the compounds disclosed in the previously described Korean Patent Nos. 47728, 47754, 47755 and 47756, i.e., cephalosporin compounds containing an optionally substituted pyrimidiniumthiomethyl group having a positive-charged structure on C-3 position have high antibacterial activity.
As one of such attempts we have tried to introduce a new substituent into C-7 position without any change in the C-3 substituent. As a result, we have identified that cephalosporin compounds having (Z)-2-(2-aminothiazol-4-yl)-2-(.alpha.-carboxy substituted phenylmethoxyimino)acetamido group on 7-.beta. position and, at the same time, 3-substituted 4-aminopy-rimidiniumthiomethyl on C-3 position exhibit a potent antibacterial activity against various pathogenic organisms including .beta.-lactamse producing gram-negative strains and further have a more improved pharmacokinetic property. Thus, now we have completed the present invention.
Therefore, it is an object of the present invention to provide a novel cephalosporin compound having the general formula (I), as defined above, which has a potent antimicrobial activity, broad antibacterial spectrum and improved pharmacokinetic properties.
It is a further object of the present invention to provide a process for preparing the novel cephalosporin compound of formula (I).
Further, it is another object of the present invention to provide a pharmaceutical composition containing the novel cephalosporin compound of formula (I) as an active ingredient.